Severe developmental abnormalities in rat cerebellar DNA synthesis and thymidine kinase activity have been found in the conditions of hyperthyroidism, hypothyroidism, hyperglucocorticoidism, and undernutrition. This proposal is to continue studies of the effects of these conditions upon enzymes critical to the incorporation of pyrimidines into DNA in developing rat brain, and to study the interrelationships between circulating corticosterone, rat growth hormone (rGH), and rat thyroid stimulating hormone (rTSH) in each condition. DNA synthesis requires incorporation of pyrimidine nucleotides via de novo, salvage (reutilization), and interrelating pathways. It is our hypothesis that activities of the de novo pathway enzyme aspartate transcarbamylase, the salvage pathway enzyme uridine kinase, and the interconverting enzyme thymidylate synthetase are affected, as is thymidine kinase, by thyroid and adrenal glucocorticoid hormones as well as by undernutrition, and that each experimental condition results in abnormal short and long term effects on the hypothalamic-pituitary-adrenal and thyroid axes. To test the hypotheses, the developmental curves of each enzyme in normal rat cerebellum will be compared with curves established from cerebella of animals rendered hyperthyroid, hypothyroid, hyperglucocorticoid, or undernourished. The cerebellum will be used because of its rapid early postnatal increase in DNA and its ease in dissection and biochemical study. The experiments designed for each endocrinopathy will be accompanied by parallel studies of the short and long term effects of the stimulus on circulating corticosterone, rGH, and rTSH, as well as the effects on circadian rhythms and response to stress. Results from these experiments should lead to a better understanding of the interrelationships between hormones, enzyme systems during development, brain morphology, and permanent effects on hypothalamic-pituitary-end organ function. The elucidation of such relationships may clarify the biochemical pathology underlying the brain damage in human perinatal thyroid dysfunction and undernutrition, and provide data for further understanding of the biochemical effects upon the nervous system of exogenous glucocorticoid administration.